Qa:Tla genes specify glycoproteins that comprise approximately 45,000 (heavy chain) and 12,000 (beta 2M) dalton subunits and thus are structurally akin to H-2. The Qa:Tla members of this molecular family are distinguished by highly restricted developmental expression and by instances of null-allelism, modulation by antibody, and aberrant expression on malignant cells. We propose an extensive collaborative study of the basis of these distinctive features, combining immunogenetic and biochemical methods, with emphasis on microsequencing (primary structure). The first system chosen for detailed analysis is TL, isolated with a monoclonal TL.2 antibody of proven precipitating capacity. Full account is taken of reported failures to sequence TL (themselves a hint of significant H-2:TL structural differences); reasons for these failures are proposed, and matched with procedures to overcome or circumvent the biochemical problems implied. Major segments will be ordered by polypeptide fragmentation, disulfide cleavage, and N-terminal sequencing. Restricted proteolysis with trypsin and papain will be used to isolate surface-disposed H-chain pieces. Allied approaches include comparative peptide mapping to reveal disparity due to TL haplotypic variation and to aberrant TL expression by malignant cells; (source material: thymocytes, including Tla-heterozygotes; and leukemia cells, including variant and non-variant lines immuno-selected for deletion of a critical Tla haplotype). A related goal is delineation of the Qa:Tla region in terms of assignment of Qa:Tl antigens throughout an ascertained set of approximately 45,000-dalton/beta 2M products. Working collaboration of our laboratories has been tested in a preliminary microsequencing exercise. The applicant's joint experience and facilities, in serological immunogenetics and relevant biochemistry, coupled with a fully operational hybridoma program, present an exceptional opportunity for a major commitment to the comparative chemistry of non-H-2 approximately 45,000 dalton/beta 2M glycoproteins of chromosome 17.